Targeting the EGFR-PI3K/mTOR Signaling Circuitry: A Network-Based Approach for Oral Cancer Precision Therapy

项目摘要 目前，口腔鳞状细胞癌(OSCC)尚无有效的靶向治疗方法，包括 口腔和口咽癌，这是一种每年导致全世界约30万人死亡的疾病。那里 迫切需要开发新的治疗方案来预防和治疗口腔鳞癌。一个令人震惊的发现来自 最近对口腔鳞状细胞癌基因组图谱的深度测序显示，基因具有显著的多样性和多样性 这种恶性病变的改变。然而，正在显现的图景是，大多数只属于几个主要驱动因素 生物学过程，包括特别强调异常激活的有丝分裂信号。 PI3K/mTOR通路。其中，编码PI3Kα催化亚基的PIK3CA是最常见的 口腔鳞状细胞癌中癌基因突变(~20%)，其中HPV相关肿瘤显著丰富(25%)。我们的团队 专注于推动口腔鳞状细胞癌启动和进展的致癌信号电路的研究，旨在 为口腔鳞癌的预防和治疗寻找新的可用药靶点。这些努力使我们很早就发现了 PI3K/mTOR信号通路的持续激活是最常见的失调信号 在口腔鳞状细胞癌中的作用机制，以及抑制PI3K/mTOR在一大系列 基因定义和化学诱导的口腔鳞状细胞癌模型。这些发现为发射 一项针对口腔鳞癌mTOR的多机构II期临床试验(NCT01195922)，最近 完成并取得了令人鼓舞的成果。然而，80%的口腔鳞癌病变缺乏驱动程序PIK3CA突变， 到目前为止，我们还不能预测在 单个肿瘤，这可能有助于解释PI3K/mTORi在非选择性晚期患者先前治疗失败的原因 口腔鳞癌患者。我们还表明，PIK3CA突变可能是西妥昔单抗耐药的原因，这可能是 被mTOR抑制所克服。我们将研究联合靶向EGFR的治疗潜力- 基于PI3K/mTOR网络亚型遗传分层的PI3K/mTOR信令电路 结合免疫肿瘤学药物，目标是开发新的精确治疗方法 OSCC。为此，我们将利用关于OSCC基因组图景的新信息来a)确定 PIK3CA缺失的口腔鳞癌皮损中PI3K/mTOR活性的改变及其意义 对西妥昔单抗耐药性和敏感性的贡献，b)识别与以下相关的新系统漏洞 西妥昔单抗和PI3K/mTORi敏化和c)建立靶向和联合靶向EGFR的影响- PI3K/mTOR信号网络在肿瘤和免疫微环境中的作用及其对新型免疫的反应 肿瘤科的特工。最终，我们的努力将a)通过以下途径克服EGFR-PI3K/mTORi耐药机制 基于网络的共同靶向策略，b)通过以下方式提高新型免疫检查点抑制剂的效力 以致癌回路为靶点，以及c)为未来患者选择提供口腔鳞癌分子分层的信息 精确和免疫肿瘤学试验。

Project Summary There are currently no effective targeted therapies for oral squamous cell carcinoma (OSCC), which includes cancers of the oral cavity and oropharynx, a disease that results in ~300,000 deaths each year worldwide. There is an urgent need to develop new therapeutic options to prevent and treat OSCC. A striking finding from the recent deep sequencing of the OSCC genomic landscape was the remarkable multiplicity and diversity of genetic alterations in this malignancy. The emerging picture, however, is that most fall within only a few major driver biological processes, including mitogenic signaling with particular emphasis on aberrant activation of the PI3K/mTOR pathway. Among them, PIK3CA, encoding the PI3Kα catalytic subunit, is the most commonly mutated oncogene in OSCC (~20%), with a significant enrichment in (HPV)-associated tumors (25%). Our team has focused on the study of oncogenic signaling circuitries driving OSCC initiation and progression, aimed at identifying novel druggable targets for OSCC prevention and treatment. These efforts led to our early discovery that the persistent activation of the PI3K/mTOR signaling circuitry is the most frequent dysregulated signaling mechanism in OSCC, and that PI3K/mTOR inhibition exerts potent antitumor activity in a large series of genetically-defined and chemically-induced OSCC models. These findings provided the rationale for launching a multi-institutional Phase II clinical trial (NCT01195922), targeting mTOR in OSCC, which was recently completed and achieved encouraging results. However, 80% of the OSCC lesions lack driver PIK3CA mutations, and to date, we cannot predict the sensitivity or resistance to EGFRi and PI3K/mTORi in the context of an individual tumor, which may help explain prior treatment failures with PI3K/mTORi in unselected advanced OSCC patients. We have also shown that PIK3CA mutations may underlie cetuximab resistance, which can be overcome by mTOR inhibition. We will investigate the therapeutic potential of co-targeting the EGFR- PI3K/mTOR signaling circuitry based on the genetic stratification of PI3K/mTOR network subtypes, alone or combined with immune oncology agents with the goal to develop novel precision therapeutic approaches for OSCC. To this end, we will exploit the emerging information about the OSCC genomic landscape to a) identify alterations driving PI3K/mTOR activation in the OSCC lesions that lack PIK3CA mutation and explore their contribution to cetuximab resistance and sensitivity, b) identify novel systems vulnerabilities associated with cetuximab and PI3K/mTORi sensitization and c) establish the impact of targeting and co-targeting the EGFR- PI3K/mTOR signaling network on the tumor and immune microenvironment, and response to novel immune oncology agents. Ultimately, our efforts will a) overcome EGFR-PI3K/mTORi resistance mechanisms via network-based co-targeting strategies, b) increase the efficacy of novel immune checkpoint inhibitors by targeting oncogenic circuities, and c) inform the molecular stratification of OSCC for patient selection in future precision and immune oncology trials.